Rapid Response to Cyclosporin A and Favorable Renal Outcome in Nongenetic Versus Genetic Steroid-Resistant Nephrotic Syndrome

Clin J Am Soc Nephrol. 2016 Feb 5;11(2):245-53. doi: 10.2215/CJN.07370715. Epub 2015 Dec 14.

Abstract

Background and objectives: Treatment of congenital nephrotic syndrome (CNS) and steroid-resistant nephrotic syndrome (SRNS) is demanding, and renal prognosis is poor. Numerous causative gene mutations have been identified in SRNS that affect the renal podocyte. In the era of high-throughput sequencing techniques, patients with nongenetic SRNS frequently escape the scientific interest. We here present the long-term data of the German CNS/SRNS Follow-Up Study, focusing on the response to cyclosporin A (CsA) in patients with nongenetic versus genetic disease.

Design, setting, participants, & measurements: Cross-sectional and longitudinal clinical data were collected from 231 patients with CNS/SRNS treated at eight university pediatric nephrology units with a median observation time of 113 months (interquartile range, 50-178). Genotyping was performed systematically in all patients.

Results: The overall mutation detection rate was high at 57% (97% in CNS and 41% in SRNS); 85% of all mutations were identified by the analysis of three single genes only (NPHS1, NPHS2, and WT1), accounting for 92% of all mutations in patients with CNS and 79% of all mutations in patients with SRNS. Remission of the disease in nongenetic SRNS was observed in 78% of patients after a median treatment period of 2.5 months; 82% of nongenetic patients responded within 6 months of therapy, and 98% of patients with nongenetic SRNS and CsA-induced complete remission (normalbuminemia and no proteinuria) maintained a normal renal function. Genetic SRNS, on the contrary, is associated with a high rate of ESRD in 66% of patients. Only 3% of patients with genetic SRNS experienced a complete remission and 16% of patients with genetic SRNS experienced a partial remission after CsA therapy.

Conclusions: The efficacy of CsA is high in nonhereditary SRNS, with an excellent prognosis of renal function in the large majority of patients. CsA should be given for a minimum period of 6 months in these patients with nongenetic SRNS. In genetic SRNS, response to CsA was low and restricted to exceptional patients.

Keywords: FSGS; NPHS1; NPHS2; WT1; cyclosporine A; humans; kidney failure, chronic; mutation; steroid resistant nephrotic syndrome.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Austria
  • Biopsy
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Cyclosporine / adverse effects
  • Cyclosporine / therapeutic use*
  • DNA Mutational Analysis
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Germany
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Infant
  • Intracellular Signaling Peptides and Proteins / genetics
  • Kidney / drug effects*
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Failure, Chronic / diagnosis
  • Kidney Failure, Chronic / genetics
  • Longitudinal Studies
  • Male
  • Membrane Proteins / genetics
  • Mutation
  • Nephrotic Syndrome / congenital*
  • Nephrotic Syndrome / diagnosis
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / physiopathology
  • Phenotype
  • Recovery of Function
  • Remission Induction
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • WT1 Proteins / genetics

Substances

  • Immunosuppressive Agents
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • WT1 Proteins
  • WT1 protein, human
  • nephrin
  • Cyclosporine

Supplementary concepts

  • Nephrotic syndrome, idiopathic, steroid-resistant